Phase I-II study of epirubicin in multiple myeloma.

Forty patients with relapsed (26) or refractory (14) myeloma were treated with epirubicin of doses of 75, 90, 105, and 120 mg/m2 in groups of 6 or more patients to test for response, maximum tolerated dose, and toxicity. Thirteen patients had received prior doxorubicin and were included in the dose findings part of the study only. Staging was I (1), II (5), and III (34). Partial responses were seen in 5 patients (18.5%) (duration 1.5, 2, 2.5, 10, and 18 months) not previously treated with doxorubicin. No responses were seen in patients treated with prior anthracycline. Responses were not dependent upon dose level of epirubicin. Median nadir white blood cell count at the four-dose levels were 2,300, 1,000, 1,600, and 1,700/mm3 with median nadir granulocyte counts of 897, 720, 688, and 192/mm3. Fever/neutropenia was infrequently observed at the three lower dose levels but occurred in 6 of 10 patients at 120 mg/m2. Platelet nadirs were 110,000, 83,000, 169,000, and 42,000/mm3. Nonhematological toxicity was not dose dependent and included alopecia (100%), nausea/vomiting (40%), and stomatitis (25%). Six patients had greater than or equal to 0.10 changes in the resting ejection fraction with one patient developing congestive heart failure that responded to medical management. This patient had received prior doxorubicin and had a history of myocardial infarction. Epirubicin can produce remissions in patients with previously treated myeloma who have not received prior doxorubicin. Since the response rate was not enhanced at 120/m2 and since fever/neutropenia was seen regularly at this dose level, the recommended dose for further study is 105 mg/m2.

Phase II study of aclarubicin in acute myeloblastic leukemia.

Aclarubicin is a new anthracycline antibiotic that produces substantially less cardiotoxicity in animals that does doxorubicin. Based upon prior Phase I and II trials in leukemia, a Phase II study in acute myeloblastic leukemia was developed to assess the response rate and toxicity in previously treated patients. Forty patients received aclarubicin 100 mg/m2 per day X 3 with repeated course on days 14-16 if marrow hypoplasia was not produced. Complete responses were achieved in 27.5% (11/40) with durations of 1.5, 2, 2, 2, 3, 3+, 4, 5+, 32+, 33+, and 34+ months. Toxic effects of this therapy included severe neutropenia and thrombocytopenia, nausea/vomiting, mucositis, and diarrhea. No patient developed significant changes in the left ventricular ejection fraction, as measured by radionuclide angiography, or any clinical cardiac symptoms. Alopecia was minimal. Aclarubicin can produce a significant response rate in previously treated patients with acute myeloblastic leukemia and should be considered for study in initial therapy.

Phase II study of rDNA alpha-2 interferon (INTRON A) in patients with multiple myeloma utilizing an escalating induction phase.

Twenty previously treated patients with multiple myeloma were treated with rDNA human alpha-2 interferon (INTRON A) in a phase II trial. Patients received an induction phase of therapy consisting of 3-100 X 10(6) IU/m2 iv given every other day pending myelosuppression. Patients then received 10 X 10(6) IU/m2 three times a week sc. In patients not responding to the iv and sc protocol, prednisone (20 mg orally) was given with each dose of INTRON A to determine whether additional responses could be produced and whether toxicity could be reduced. During the sc phases of therapy, INTRON A was escalated pending hematologic and nonhematologic toxicity. Three partial remissions were achieved in patients receiving the initial iv/sc therapy, and one additional patient responded when prednisone was added (durations of remission, 5, 6, 8, and 9 months). Myelosuppression was the dose-limiting toxic effect in both the iv and sc phases of therapy. Constitutional symptoms (flu-like) were seen in the majority of patients, but were tolerable. With the utilization of prednisone, flu-like symptoms were reduced in frequency and degree. Escalation of the dose of INTRON A was possible in the majority of patients when prednisone was added; however, only one patient (of seven) responded to combination therapy. INTRON A can produce remissions in 20% of patients with previously treated multiple myeloma. No improvement in the response rate was achieved utilizing a high-dose induction program. Although the dose of INTRON A could be escalated when prednisone was added, the response rate was not enhanced.

Combination chemotherapy for multiple myeloma with BCNU, cyclophosphamide, vincristine, melphalan, and prednisone (M-2 protocol).

54 consecutively referred, previously untreated patients with stage II and III multiple myeloma have been treated with the M-2 protocol. 50% of patients had a performance status of less than 50%. 13% were stage II and 87% stage III. In 50 of 54 patients (90%), and objective response according to the Myeloma Task Force was achieved; 10% of the responses have been complete (9+, 15+, 17+, 18+ and 66+ months). Remissions now range from 1 to 86+ months. The actuarial median survival determined from the initiation of therapy will exceed 4 years. Toxicity was acceptable with mild myelosuppression. These results confirm the efficacy of the M-2 protocol in multiple myeloma with regards to response rate and survival.